Project Summary/Abstract Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer-associated death in women in the United States. Over half of all breast cancers are hormone receptor positive (HR+), due to their expression of the estrogen and/or progesterone receptor (ER/PR). While ER-targeted therapies are typically successful at treating primary tumor growth, up to 40% of ER-positive tumors eventually recur and metastasize. Therefore, novel molecular targets are needed to treat recurrent and metastatic HR+ breast cancers. Our previous research identified Semaphorin 7a (SEMA7A) as a mediator of various aspects associated with HR+ breast cancer progression, including proliferation, invasion, and cell survival. SEMA7A is a signaling molecule known to drive neuronal development, immunity, and fibrosis. SEMA7A is a unique member of the semaphorin family, as it is the only semaphorin with a GPI-anchor that can be cleaved, allowing SEMA7A to be shed into the extracellular environment. This supports my proposal that SEMA7A may affect the tumor microenvironment in addition to inherent cellular processes. Analysis of multiple publicity available breast cancer patient cohorts revealed increased SEMA7A expression in breast tumors compared to normal breast tissue, as well as a significant correlation between SEMA7A expression and decreased survival. Taken together, this led me to hypothesize that SEMA7A promotes breast tumor progression and may be a novel therapeutic target. However, the molecular mechanisms behind increased SEMA7A expression and how SEMA7A signals to result in aggressive tumor cell behaviors remain unknown. The goals of this proposal are to determine: 1) how SEMA7A expression is upregulated in HR+ breast cancer, 2) how SEMA7A signaling promotes cell survival, and 3) whether SEMA7A promotes metastasis via remodeling of the blood vasculature. In aim 1, I will determine whether nuclear hormone receptors directly induce transcriptional regulation of SEMA7A. I will also examine how SEMA7A signals to induce the observed pro-survival phenotype. In aim 2, I will examine if SEMA7A promotes metastasis through blood vessel remodeling. The expected outcomes of this research will further our understanding of SEMA7A expression and signaling in HR+ breast cancer. These results will have a positive impact by characterizing a novel potential therapeutic target in HR+ breast cancer. Finally, as SEMA7A is minimally expressed in most adult tissues, we postulate this therapy will have low toxicity, making it ideal for clinical application.